Type 1 diabetes is a regulated disease as the initiation of insulitis and its progression to overt diabetes are neither immediate nor inevitable in genetically susceptible individuals. The focus of this effort is insulitis initiation - what triggers it and what sets its tone. During the last funding cycle, experiments exploiting the NOD and BDC2.5 mouse models of Type-1 diabetes provided considerable support for the following scenario of events triggering islet infiltration: A physiological ripple of islet beta-cell death produces beta-cell fragments, which are engulfed by resident dendritic cells, provoking them to migrate to the draining pancreatic lymph nodes. En route, they process beta-cell antigens and eventually display them at the cell surface loaded within major histocompatibility molecules. Once in the nodes, the dendritic cells present these antigens to naive T cells circulating through; the T cells are activated and exit to the tissues. In the pancreas, they re-encounter beta-cell-derived antigens, are restimulated and are retained. This scenario will serve as a framework for integrating the molecular and cellular processes associated with insulitis initiation. During the next funding cycle, the processes responsible for setting the tone of the islet infiltrate will be explored. Preliminary studies comparing BDC2.5/NOD mice (progressively diabetic) and BDC2.5/B6.H-2/g7 mice (immediately diabetic) have spurred the hypothesis that NK cells are important determinants of the aggressivity of the insulitic lesion. The studies proposed herein will address three major questions: 1. Are NK or CD8+ T cells really the culprits? 2. What is the basic mechanism involved - direct killing or release of a mediator? 3. Is the destructive influence NK-cell intrinsic? Answers to these questions should establish what factors dictate whether insulitis, precedes innocuously or destructively in the BDC2.5 mouse model of autoimmune diabetes Potential human relevance immediately suggests itself: might similar elements play a role in the striking increase in diagnosis of fulminant Type-1 diabetes in children under five years of age?